EXISTEN-SANOVEL

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXISTEN – SANONEL (EXISTEN – SANONEL)

Composition:

Active substance: meloxicam;

1 tablet contains 15 mg of meloxicam;

Excipients: sodium citrate, lactose monohydrate, microcrystalline cellulose, povidone, colloidal anhydrous silicon dioxide, crospovidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: elongated biconvex tablets of light yellow color with a greenish tint, with a break line on both sides.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory drugs and antirheumatic agents. Oxicams. ATC code M01A C06.

Pharmacological properties.

Pharmacodynamics.

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the enolic acid class, possessing anti-inflammatory, analgesic, and antipyretic effects.

Meloxicam has demonstrated high anti-inflammatory activity in all standard models of inflammation. As with other NSAIDs, its exact mechanism of action remains unknown. However, a common mechanism of action for all NSAIDs (including meloxicam) is inhibition of prostaglandin biosynthesis, which are mediators of inflammation.

Pharmacokinetics.

Absorption. Meloxicam is well absorbed from the gastrointestinal tract following oral administration, with an absolute bioavailability of 90% (capsules). Tablets, oral suspension, and capsules have shown bioequivalence. After single-dose administration, maximum plasma concentration is reached within 5–6 hours for solid oral dosage forms (capsules and tablets).

At steady state, stable concentrations are achieved by day 3–5 with repeated dosing. Once-daily dosing results in average plasma concentrations with relatively small peak fluctuations: within 0.4–1.0 µg/mL for the 7.5 mg dose and 0.8–2.0 µg/mL for the 15 mg dose, respectively (Cmin and Cmax at steady state, respectively). Average steady-state plasma concentrations of meloxicam are reached within 5–6 hours for tablets, capsules, and oral suspension, respectively.

Concomitant food intake or administration of inorganic antacids does not affect drug absorption.

Distribution. Meloxicam is highly bound to plasma proteins, primarily to albumin (99%). Meloxicam penetrates into synovial fluid, where its concentration is approximately half that in plasma. The volume of distribution is low, averaging 11 L after intramuscular or intravenous administration, with individual variations ranging from 7 to 20%. The volume of distribution after multiple oral doses of meloxicam (7.5 to 15 mg) is 16 L, with a coefficient of variation from 11 to 32%.

Biotransformation. Meloxicam undergoes extensive biotransformation in the liver.

Four different metabolites of meloxicam, pharmacodynamically inactive, have been identified in urine. The main metabolite, 5’-carboxymeloxicam (60% of dose), is formed via oxidation of the intermediate metabolite 5’-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP2C9 plays a major role in metabolism, while CYP3A4 isoenzymes contribute to a lesser extent. Peroxidase activity in patients may be responsible for two other metabolites, accounting for 16% and 4% of the administered dose, respectively.

Elimination. Elimination of meloxicam occurs primarily as metabolites, excreted in equal parts in urine and feces. Less than 5% of the daily dose is excreted unchanged in feces, and a negligible amount is excreted in urine. The elimination half-life ranges from 13 to 25 hours after oral, intramuscular, and intravenous administration. Plasma clearance is approximately 7–12 mL/min after a single oral dose, intravenous, or rectal administration.

Linearity of dose. Meloxicam exhibits linear pharmacokinetics within the therapeutic dose range of 7.5 mg to 15 mg following oral and intramuscular administration.

Special patient groups.

Patients with hepatic/renal impairment. Mild to moderate hepatic and renal impairment do not significantly affect the pharmacokinetics of meloxicam. Patients with moderate renal impairment had significantly higher total clearance. Reduced plasma protein binding was observed in patients with end-stage renal disease. In end-stage renal disease, increased volume of distribution may lead to higher concentrations of free meloxicam. Daily dose should not exceed 7.5 mg (see section "Dosage and administration").

Elderly patients. In elderly male patients, average pharmacokinetic parameters are similar to those in young male volunteers. In elderly female patients, AUC values are higher and elimination half-life is longer compared to young volunteers of both sexes. Average plasma clearance at steady state in elderly patients was slightly lower than in young volunteers.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of osteoarthritis flare-ups.

Long-term symptomatic treatment of rheumatoid arthritis and ankylosing spondylitis.

Contraindications.

• Hypersensitivity to meloxicam or any of the excipients of the medicinal product, or to active substances with similar actions, such as NSAIDs, acetylsalicylic acid. Meloxicam should not be administered to patients who have experienced asthma symptoms, nasal polyps, angioedema, or urticaria after taking acetylsalicylic acid or other NSAIDs;
• Third trimester of pregnancy (see section "Use during pregnancy or breastfeeding");
• Age under 16 years;
• Gastrointestinal bleeding or perforation associated with previous NSAID therapy, in medical history;
• Active or recurrent peptic ulcer/hemorrhage in medical history (two or more separate confirmed episodes of ulcer or bleeding);
• Severe hepatic insufficiency;
• Severe renal insufficiency without dialysis;
• Gastrointestinal bleeding, cerebrovascular bleeding in medical history, or other coagulation disorders;
• Severe heart failure;
• Perioperative pain in coronary artery bypass grafting (CABG).

Interaction with other medicinal products and other forms of interaction.

Studies on interactions were conducted only in adults.

Risks associated with hyperkalemia

Certain medicinal products or therapeutic classes may promote hyperkalemia: potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), (low molecular weight or unfractionated) heparins, cyclosporine, tacrolimus, and trimethoprim.

The onset of hyperkalemia may depend on associated factors. The risk of developing hyperkalemia increases if the above-mentioned medicinal products are used concomitantly with meloxicam.

Pharmacodynamic interactions.

Other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid

≥ 3 g/dose. Combination with other NSAIDs is not recommended (see section "Special precautions for use"), including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g per dose or ≥ 3 g total daily dose).

Glucocorticosteroids (e.g. glucocorticoids). Concomitant use with corticosteroids requires caution due to an increased risk of gastrointestinal bleeding or ulceration.

Anticoagulants or heparin used in geriatric practice or at therapeutic doses. Significantly increases the risk of bleeding due to platelet function inhibition and gastroduodenal mucosal damage. NSAIDs may enhance the effects of anticoagulants such as warfarin (see section "Special precautions for use"). Concomitant use of NSAIDs and anticoagulants or heparin in geriatric practice or at therapeutic doses is not recommended (see section "Special precautions for use").

In other cases (e.g., prophylactic doses), heparin use requires caution due to an increased risk of bleeding. Careful monitoring of INR (International Normalized Ratio) is necessary if this combination cannot be avoided.

Thrombolytic and antiplatelet agents: Increased risk of bleeding due to platelet function inhibition and gastroduodenal mucosal damage.

Selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding.

Diuretics, ACE inhibitors, and angiotensin II antagonists. NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of ACE inhibitors or angiotensin II antagonists and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, combination therapy should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of combined therapy and periodically thereafter (see section "Special precautions for use").

Other antihypertensive agents (e.g., beta-blockers). As with the drugs listed below, a possible reduction in the antihypertensive effect of beta-blockers may occur (due to inhibition of vasodilatory prostaglandins).

Calcineurin inhibitors (e.g., cyclosporine, tacrolimus). The nephrotoxicity of calcineurin inhibitors may be enhanced by NSAIDs due to mediation of renal prostaglandin effects. Renal function should be monitored during treatment. Careful monitoring of renal function is recommended, especially in elderly patients.

Intrauterine contraceptive devices. NSAIDs may reduce the effectiveness of intrauterine contraceptive devices. There have been previous reports of reduced efficacy of intrauterine contraceptive devices with NSAID use, but this requires further confirmation.

Deferasirox.

Concomitant use of meloxicam and deferasirox may increase the risk of gastrointestinal adverse reactions. Caution should be exercised when combining these medicinal products.

Pharmacokinetic interaction: effect of meloxicam on the pharmacokinetics of other medicinal products.

Lithium. Data exist for NSAIDs increasing plasma lithium concentrations (due to reduced renal excretion of lithium), which may reach toxic levels. Concomitant use of lithium and NSAIDs is not recommended (see section "Special precautions for use"). If combination therapy is necessary, plasma lithium levels should be closely monitored at the start of treatment, during dose adjustment, and upon discontinuation of meloxicam.

Methotrexate. NSAIDs may reduce tubular secretion of methotrexate, thereby increasing its plasma concentration. For this reason, concomitant use of NSAIDs is not recommended in patients receiving high-dose methotrexate (over 15 mg/week) (see section "Special precautions for use"). The risk of interaction between NSAIDs and methotrexate should also be considered in patients receiving low-dose methotrexate, particularly those with impaired renal function. If combination therapy is required, blood parameters and renal function should be monitored. Caution is advised if NSAID and methotrexate are taken for three consecutive days, as methotrexate plasma levels may rise and toxicity may be enhanced. Although the pharmacokinetics of methotrexate (15 mg/week) were not affected by concomitant meloxicam treatment, hematological toxicity of methotrexate may increase during NSAID therapy (see information provided above) (see section "Adverse reactions").

Pemetrexed. When meloxicam is used concomitantly with pemetrexed in patients with mild to moderate renal impairment (creatinine clearance from 45 to 79 mL/min), meloxicam administration should be withheld for 5 days before, on the day of, and 2 days after pemetrexed infusion. If combination of meloxicam with pemetrexed is necessary, patients should be closely monitored, particularly for myelosuppression and gastrointestinal adverse reactions. Concomitant use of meloxicam with pemetrexed is not recommended in patients with severe renal impairment (creatinine clearance below 45 mL/min).

In patients with normal renal function (creatinine clearance ≥ 80 mL/min), a dose of 15 mg meloxicam may reduce pemetrexed elimination and thus increase the frequency of pemetrexed-related adverse reactions. Therefore, caution should be exercised when prescribing 15 mg meloxicam concomitantly with pemetrexed in patients with normal renal function (creatinine clearance ≥ 80 mL/min).

Pharmacokinetic interaction: effect of other medicinal products on the pharmacokinetics of meloxicam.

Cholestyramine. Cholestyramine accelerates meloxicam elimination due to disruption of enterohepatic circulation, resulting in a 50% increase in meloxicam clearance and a reduction in half-life to 13±3 hours. This interaction is clinically significant.

No clinically significant pharmacokinetic interaction was observed with concomitant administration of antacids, cimetidine, or digoxin.

Pharmacokinetic interaction: effect of combination of meloxicam and other medicinal products on pharmacokinetics.

Oral antidiabetic agents (sulfonylurea derivatives, nateglinide)

Meloxicam is almost entirely eliminated via hepatic metabolism, approximately two-thirds mediated by cytochrome P450 (CYP) enzymes (mainly CYP 2C9 and secondary pathway CYP 3A4) and one-third via other pathways, such as peroxidase oxidation. Potential pharmacokinetic interactions should be considered when meloxicam is administered concomitantly with medicinal products that strongly inhibit or are metabolized by CYP 2C9 and/or CYP 3A4. Interactions mediated by CYP 2C9 may be expected when combined with medicinal products such as oral antidiabetic agents (sulfonylurea derivatives, nateglinide); this interaction may lead to increased plasma levels of these agents and meloxicam. Patients receiving meloxicam and sulfonylurea or nateglinide should be closely monitored for the development of hypoglycemia.

Special precautions for use.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks below).

The recommended maximum daily dose should not be exceeded if there is insufficient therapeutic effect, and additional NSAIDs should not be used concomitantly, as this may increase toxicity without proven therapeutic benefits. Concomitant use of meloxicam with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Meloxicam is not suitable for the treatment of patients requiring relief from acute pain.

If no improvement is observed after several days, the clinical benefits of continued treatment should be re-evaluated.

Caution should be exercised in patients with a history of esophagitis, gastritis, and/or peptic ulcer to ensure complete treatment prior to initiating meloxicam therapy. Patients receiving meloxicam and those with such history should be regularly monitored for possible recurrence.

Gastrointestinal disorders.

As with other NSAIDs, potentially fatal gastrointestinal bleeding, ulceration, or perforation may occur at any time during treatment, with or without prior symptoms or serious gastrointestinal disease history.

The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increased NSAID doses, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Such patients should start treatment with the lowest effective dose. For these patients, combination therapy with protective agents (such as misoprostol or proton pump inhibitors) should be considered, as well as for patients requiring concomitant use of low-dose aspirin or other drugs increasing gastrointestinal risks (see information below and section "Interaction with other medicinal products and other forms of interaction").

Patients with a history of gastrointestinal toxicity, especially elderly patients, should be informed about any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially during initial stages of treatment.

Caution should be exercised in patients who are concomitantly using drugs that may increase the risk of ulceration or bleeding, including heparin as a full anticoagulant therapy or in geriatric practice, anticoagulants such as warfarin, or other non-steroidal anti-inflammatory drugs, including acetylsalicylic acid at anti-inflammatory doses (≥ 1 g per dose or ≥ 3 g total daily dose) (see section "Interaction with other medicinal products and other forms of interaction").

If gastrointestinal bleeding or ulceration occurs in patients taking meloxicam, treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as these conditions may be exacerbated (see section "Adverse reactions").

Hepatic disorders.

Up to 15% of patients taking NSAIDs (including meloxicam) may experience elevated levels of one or more liver function tests. These laboratory abnormalities may progress, remain unchanged, or be transient during continued treatment. Marked elevations of ALT or AST (approximately three times or more above normal) were observed in 1% of patients during clinical trials with NSAIDs. Additionally, rare cases of severe hepatic reactions, including jaundice and fulminant fatal hepatitis, liver necrosis, and hepatic failure, some of which were fatal, have been reported.

Patients with symptoms or suspected hepatic dysfunction or those with abnormal liver function tests should be evaluated for signs of more severe hepatic failure during meloxicam therapy. If clinical signs and symptoms suggest liver disease or if systemic manifestations of disease (e.g., eosinophilia, rash, etc.) occur, meloxicam should be discontinued.

Cardiovascular disorders.

Close monitoring is recommended for patients with arterial hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema have been observed during NSAID therapy.

In patients with risk factors, clinical monitoring of blood pressure is recommended at the beginning of therapy, especially at the start of meloxicam treatment.

Data from studies and epidemiological evidence suggest that the use of some NSAIDs (particularly at high doses and during long-term treatment) may be associated with a small increased risk of vascular thrombotic events (e.g., myocardial infarction or stroke). There is insufficient data to exclude such risk for meloxicam.

Meloxicam therapy should be initiated only after careful consideration in patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. A similar assessment is required before initiating long-term treatment in patients with cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which may be fatal. The risk increases with duration of use. Patients with cardiovascular disease or cardiovascular risk factors may have an increased risk.

Skin disorders.

Serious skin reactions, some of which were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been observed very rarely with NSAID use (see section "Adverse reactions"). The highest risk of such reactions occurs early in treatment, with most cases appearing within the first month of therapy. At the first appearance of skin rash, mucosal lesions, or other signs of hypersensitivity, meloxicam use should be discontinued. Prompt diagnosis and discontinuation of any drug that may cause severe skin injury—Stevens-Johnson syndrome or toxic epidermal necrolysis—are crucial, as early intervention improves prognosis. If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis while taking meloxicam, the drug must not be re-administered at any time in the future.

Cases of fixed drug eruption have been reported with meloxicam use.

Meloxicam should not be re-prescribed to patients with a history of fixed drug eruption associated with meloxicam use.

Potential cross-reactivity may occur with other oxicams.

Anaphylactic reactions.

As with other NSAIDs, anaphylactic reactions may occur in patients without known sensitivity to meloxicam. Meloxicam should not be used in patients with aspirin triad. This symptomatic complex occurs in patients with asthma who have a history of rhinitis with or without nasal polyps or who experienced severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency measures should be taken if an anaphylactoid reaction occurs.

Liver parameters and renal function.

As with treatment with most NSAIDs, isolated cases of elevated serum transaminases, elevated serum bilirubin, or other liver function parameters, as well as increased serum creatinine and blood urea nitrogen, and other laboratory abnormalities have been reported. In most cases, these abnormalities were mild and transient. If significant or persistent abnormalities are confirmed, meloxicam should be discontinued and follow-up tests performed.

Functional renal failure.

NSAIDs, by inhibiting the vasodilatory effect of renal prostaglandins, may induce functional renal failure due to decreased glomerular filtration. This adverse effect is dose-dependent. Careful monitoring of diuresis and renal function is recommended at the beginning of treatment or after dose increase in patients with the following risk factors:

• advanced age;
• concomitant use with ACE inhibitors, angiotensin II antagonists, sartans, diuretics (see section "Interaction with other medicinal products and other forms of interaction");
• hypovolemia (of any origin);
• congestive heart failure;
• renal insufficiency;
• nephrotic syndrome;
• lupus nephropathy;
• severe hepatic dysfunction (serum albumin < 25 g/L or ≥ 10 according to Child-Pugh classification).

In rare cases, NSAIDs may lead to interstitial nephritis, glomerulonephritis, renal medullary necrosis, or nephrotic syndromes.

The dose of meloxicam in patients with end-stage renal failure on dialysis should not exceed 7.5 mg. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance > 25 mL/min).

Sodium, potassium, and water retention.

NSAIDs may enhance sodium, potassium, and water retention and may interfere with the natriuretic effects of diuretics. Additionally, a reduction in the antihypertensive effect of antihypertensive drugs may occur (see section "Interaction with other medicinal products and other forms of interaction"). As a result, edema, heart failure, or arterial hypertension may be accelerated or exacerbated in susceptible patients. Therefore, clinical monitoring is recommended for patients with such risks (see sections "Dosage and administration" and "Contraindications").

Hyperkalemia.

Hyperkalemia may be promoted by diabetes mellitus or concomitant use of drugs that increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). In such cases, regular monitoring of potassium levels is required.

Other warnings and safety measures.

Adverse reactions are often less well tolerated in elderly, frail, or debilitated patients, who require careful monitoring. As with other NSAIDs, caution is advised in elderly patients, in whom reduced renal, hepatic, and cardiac function is more likely. Elderly patients have a higher frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal (see section "Dosage and administration").

Meloxicam, like any other NSAID, may mask symptoms of infectious diseases.

The use of meloxicam may negatively affect fertility and is not recommended for women wishing to become pregnant. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered (see section "Use during pregnancy or breastfeeding").

Tablets contain lactose; therefore, this product is not recommended for patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Masking of inflammation and fever.

The pharmacological action of meloxicam in reducing fever and inflammation may complicate diagnosis in suspected non-infectious painful conditions.

Corticosteroid therapy.

Meloxicam cannot be considered a substitute for corticosteroids in the treatment of corticosteroid deficiency.

Hematological effects.

Anemia may occur in patients receiving NSAIDs, including meloxicam. This may be related to fluid retention, occult gastrointestinal bleeding, or a partially unexplained effect on erythropoiesis. Patients undergoing long-term NSAID treatment, including meloxicam, should have hemoglobin or hematocrit monitored if symptoms or signs of anemia are present.

NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, short-term, and reversible. Close monitoring is required for patients taking meloxicam who may have adverse effects on platelet function, including coagulation disorders, or those receiving anticoagulants.

Use in patients with asthma.

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma is associated with severe bronchospasm, which may be fatal. Due to cross-reactivity, including bronchospasm, between aspirin and other NSAIDs, meloxicam should not be used in patients sensitive to aspirin and should be used cautiously in patients with asthma.

Use during pregnancy or breastfeeding.

Fertility. Meloxicam, like other drugs that inhibit cyclooxygenase/prostaglandin synthesis, may negatively affect reproductive function and is not recommended for women wishing to become pregnant. Therefore, for women planning pregnancy or undergoing infertility evaluation, discontinuation of meloxicam should be considered.

Pregnancy. Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic and fetal development. Epidemiological data suggest an increased risk of miscarriage and congenital heart defects and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of heart defects increased from less than 1% to about 1.5%. This risk is believed to increase with higher doses and longer duration of treatment.

From the 20th week of pregnancy, use of Existen-sanovel may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of ductus arteriosus constriction after treatment in the second trimester, most of which resolved after treatment cessation. Therefore, meloxicam should not be prescribed during the first and second trimesters of pregnancy unless necessary. If meloxicam is used by a woman trying to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after meloxicam exposure for several days starting from the 20th gestational week. Meloxicam use should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose risks to the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

Possible risks at the end of pregnancy for mother and newborn:

• possible prolongation of bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• inhibition of uterine contractions leading to delayed or prolonged labor.

Therefore, meloxicam is contraindicated during the third trimester of pregnancy.

Breastfeeding. Although specific data on meloxicam are lacking, it is known that NSAIDs can pass into breast milk. Therefore, use is not recommended for women who are breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

No specific studies on the effect of meloxicam on the ability to drive or operate machinery have been conducted. However, based on its pharmacodynamic profile and observed adverse reactions, meloxicam is likely to have no effect or only a minor effect on such activities. Nevertheless, patients experiencing visual disturbances, including blurred vision, dizziness, somnolence, vertigo, or other central nervous system (CNS) disorders, are advised to refrain from driving or operating machinery.

Dosage and Administration

Administer orally.

The total daily dose should be taken once daily, with food, and washed down with water or another liquid.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use"). The patient's need for symptomatic relief and response to treatment should be periodically reassessed.

Exacerbation of osteoarthritis

7.5 mg/day (half a 15 mg tablet). If necessary, the dose may be increased to 0.5 mg/day (1 tablet of 15 mg).

Rheumatoid arthritis, ankylosing spondylitis

15 mg/day (1 tablet of 15 mg).

See also section "Special Patient Populations" below.

The dose may be reduced to 7.5 mg/day (half a 15 mg tablet) based on therapeutic response.

DO NOT EXCEED THE DOSE OF 15 mg/day.

Special Patient Populations

Elderly patients and patients at increased risk of adverse reactions

The recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg daily. Patients at increased risk of adverse reactions should start treatment at 7.5 mg daily (see section "Special Warnings and Precautions for Use").

Renal impairment

In patients with severe renal impairment on dialysis, the dose should not exceed 7.5 mg daily. Dose reduction is not required in patients with mild to moderate renal impairment (i.e., patients with creatinine clearance above 25 mL/min) (for patients with severe renal impairment not on dialysis, see section "Contraindications").

Hepatic impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment (for patients with severe hepatic impairment, see section "Contraindications").

Children

Meloxicam is contraindicated in children under 16 years of age (see section "Contraindications").

Overdose

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding may occur. Severe poisoning may lead to arterial hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular failure, and cardiac arrest. Anaphylactoid reactions have been reported during therapeutic use of NSAIDs and may also occur in cases of overdose.

In the event of NSAID overdose, symptomatic and supportive treatment is recommended. Studies have shown that elimination of meloxicam can be accelerated by administering 4 oral doses of cholestyramine three times daily.

Side effects.

Data from studies and epidemiological data suggest that the use of certain NSAIDs (especially at high doses and during long-term treatment) may be associated with a small increased risk of vascular thrombotic events (e.g., myocardial infarction or stroke) (see section "Special precautions").

Edema, arterial hypertension, and heart failure have been observed during NSAID therapy.

Most of the adverse effects observed are gastrointestinal in origin. Peptic ulcer, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients (see section "Special precautions"). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn's disease have been reported after administration (see section "Special precautions"). Gastritis has been observed less frequently.

Criteria for assessing the frequency of adverse drug reactions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (<1/10,000); not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

uncommon – anemia;

rare – blood test abnormalities (including changes in leukocyte count), leukopenia, thrombocytopenia.

Very rare cases of agranulocytosis have been reported (see "Specific serious and/or common adverse reactions").

Immune system disorders:

uncommon – allergic reactions, excluding anaphylactic or anaphylactoid reactions;

not known – anaphylactic reaction, anaphylactoid reaction, including shock.

Psychiatric disorders:

rare – mood changes, nightmares;

not known – confusion, disorientation, insomnia.

Nervous system disorders:

common – headache;

uncommon – dizziness, somnolence.

Eye disorders:

rare – visual disturbances including blurred vision; conjunctivitis.

Ear and labyrinth disorders:

uncommon – dizziness;

rare – tinnitus.

Cardiac disorders:

rare – palpitations.

Heart failure associated with NSAID therapy has been reported.

Vascular disorders:

uncommon – increased blood pressure (see section "Special precautions"), flushing.

Respiratory, thoracic and mediastinal disorders:

rare – asthma in patients with aspirin or other NSAID allergy;

not known – upper respiratory tract infections, cough.

Gastrointestinal disorders:

very common – dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhea;

uncommon – occult or macroscopic gastrointestinal bleeding, stomatitis, gastritis, eructation;

rare – colitis, gastroduodenal ulcer, esophagitis;

very rare – gastrointestinal perforation;

not known – pancreatitis.

Gastrointestinal bleeding, ulceration, or perforation may be severe and potentially fatal, particularly in elderly patients (see section "Special precautions").

Hepatobiliary disorders:

uncommon – abnormalities in liver function tests (e.g., elevated transaminases or bilirubin);

very rare – hepatitis;

not known – jaundice, liver failure.

Skin and subcutaneous tissue disorders:

uncommon – angioneurotic edema, pruritus, rash;

rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria;

very rare – bullous dermatitis, erythema multiforme;

not known – photosensitivity reactions, exfoliative dermatitis, fixed drug eruption (see section "Special precautions").

Renal and urinary disorders:

uncommon – sodium and water retention, hyperkalemia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"), changes in renal function parameters (elevated creatinine and/or blood urea);

very rare – acute renal failure, particularly in patients with risk factors (see section "Special precautions");

not known – urinary tract infections, changes in micturition frequency.

General disorders and administration site conditions:

uncommon – edema, including peripheral edema;

not known – influenza-like symptoms.

Musculoskeletal and connective tissue disorders:

not known – arthralgia, back pain, joint signs and symptoms.

Specific serious and/or common adverse reactions.

Very rare cases of agranulocytosis have been reported in patients treated with meloxicam and other potentially myelotoxic medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Adverse reactions not observed during use of the medicinal product but generally recognized as typical for other compounds of the class.

Organic renal damage, which may lead to acute renal failure: very rare cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, and papillary necrosis have been reported (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging. 10 tablets per blister; 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Sanovel Ilac Sanayi ve Ticaret A.S.

Manufacturer's address and place of business.

Balaban Quarter, Cihangir Sokagi, No. 10, Silivri District, Istanbul 34580, Turkey.